Arachidonic acid (AA) is a 20-carbon polyunsaturated fatty acid derived from dietary sources. Oxygenated AA metabolites participate in a variety of biologic and pathological processes including inflammation, bronchial asthma, and shock. Activation of AA metabolism is initiated by the release of AA from the phospholipid pool by the action of enzymes or other mediators. The released AA can be metabolized by either the lipoxygenase pathway where AA is converted by fatty acid lipoxygenases into hydroperoxy derivatives, giving rise to leukotrienes, or the cycloxygenase pathway where a fatty acid transforms AA rapidly to the prostaglandin PGG.sub.2, which in turn is further converted enzymatically.
A protein designated 5-lipoxygenase activating protein (FLAP) appears to be necessary for cellular leuketriene synthesis (U.S. Pat. No. 5,182,367; Miller et al. (1990) Nature 343:278-281). FLAP appears to be involved in the translocation of 5-lipoxygenase from the cytosol to the membrane. Other enzymes involved with the sequential metabolism of the lipoxygenase product need to be in close relationship to the 5-lipoxygenase FLAP complex. FLAP and molecules of related structure may be essential to the activity of enzymes in the 5-lipoxygenase pathway as well as the other downstream enzymes required for leuketriene biosynthesis.
Inhibitors of the AA 5-lipoxygenase pathway have shown promise in the treatment of inflammation, asthma, and shock, with minimal side effects in pre-clinical and clinical trials (Batt, Prog. Med. Chem. 29:1-63 (1992); Larson, Ann. Pharmacother. 27:898-903 (1993)). However, their use for treating or preventing cancer has never been described.
The present invention is directed to the use of inhibitors of 5-lipoxygenase functional activity for the treatment and prevention of epithelial cell-derived cancers. The present invention is also directed to the use of inhibitors of other enzymes in the lipoxygenase pathway involved in the metabolism of AA for use in the treatment and prevention of epithelial cell-derived cancers.